Fatty acid treatment

ABSTRACT

The use in preparation of a medicament for treating and preventing the side effects of anti-cancer chemotherapy of a polyunsaturated fatty acid with a carbon chain length of 14 to 26 and with 2 to 6 double bonds in the molecule in cis or trans configuration, and a method of such treatment or prevention wherein said fatty acid is used as an active.

FIELD OF THE INVENTION

[0001] The invention relates to fatty acid treatment.

BACKGROUND

[0002] Chemotherapy, the use of drugs which aim either to kill cancercells or to stop the spread of cancer, is now one of the most widelyused types of treatment for cancer. It may be used either alone or incombination with one of the other modalities of cancer treatment,usually surgery or radiotherapy. Most chemotherapy regimes, other thanthose primarily targeted at the endocrine system such as anti-oestrogensand antiandrogens, cause important side effects. These side effectsdiffer from drug to drug, but it is now common to use two, three, fouror more drugs in combination in chemotherapy regimes and so mostchemotherapy-treated patients will experience one or more of the typicalconsequences. The side effects include nausea, vomiting, suppression ofthe immune system, suppression of white blood cells and platelets, hairloss, cardiovascular damage, lung damage, renal damage, nerve damage andmarked fatigue and malaise. Each drug has a specific range of sideeffects, some of which may be particularly important and limit the doseof the drug which can be given and so reduce the likelihood of a cure.Doxorubicin and related compounds, for example, can be severelycardiotoxic and this is a common dose-limiting side effect. Bleomycin,and to a lesser extent cyclophosphamide, can be toxic to the lungscausing fibrosis. The platinum derivatives and related compounds may bevery toxic to the nerves.

[0003] We have been developing gamma-linolenic acid (GLA) and relatedcompounds, including linoleic acid (LA), dihomogarnmalinolenic acid(DGLA), arachidonic acid (AA), stearidonic acid (SA), alpha-linolenicacid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)for the treatment of cancer. These compounds which are allpolyunsaturated lipids are cytotoxic to many cancer cells atconcentrations which do not harm normal cells and also have a range ofanti-metastatic effects which may be operative at lower concentrations.We have come to the conclusion that many unsaturated fatty acids withcarbon chain lengths from 14 to 26 and which contain two to sixunsaturated double carbon-carbon bonds which may be either in the cis orthe trans configuration can have anti-cancer actions. Other examples ofsuch fatty acids include conjugated linoleic acid and parinaric acid,but the natural n-6 and n-3 EFAS are set out in the following: n-6  EFAsn-3  EFAs 18:2n-6 18:3n-3 Linoleic acid (LA) α-linolenic acid (ALA) ↓δ-6-desaturase ↓ 18:3n-6 18:4n-3 γ-Linolenic acid (GLA) Stearidonicacid, (SA) ↓ elongation ↓ 20:3n-6 20:4n-3 Dihomo-γ-linolenic acidEicosatetraenoic acid (DGLA) ↓ δ-5-desaturase ↓ 20:4n-6 20:5n-3Arachidonic acid (AA) Eicosapentaenoic acid (EPA) ↓ elongation ↓ 22:4n-622:5n-3 Adrenic acid (AdrA) ↓ δ-4-desaturase ↓ 22:5n-6 22-6n-3Docosahexaenoic acid (DHA)

[0004] The acids, which in nature are of the all-cis configuration, aresystematically named as derivatives of the corresponding octadecanoic,eicosanoic or docosanoic acids, e.g. LA z,z-octadeca-9,12-dienoic acidor DHA z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexanoic acid, but numericaldesignations based on the number of carbon atoms, the number of centresof unsaturation and the number of carbon atoms from the end of the chainto where the unsaturation begins, such as correspondingly, 18:2 n-6 or22:6 n-3, are convenient. Initials, e.g. EPA, and shortened forms of thename e.g. eicosapentaenoic acid, are used as trivial names in someinstances.

CURRENT WORK

[0005] In a range of studies we have administered GLA, LA, EPA and DHAto patients with cancer and we are actively developing specificderivatives of these fatty acids as anti-cancer drugs. In manyinstances, the fatty acids have been given to patients who at that sametime were receiving conventional chemotherapy for their cancer. We haverepeatedly observed that many of the toxic side effects of chemotherapyare substantially reduced in patients who at the same time are receivingone or more of LA, GLA, EPA and DHA. On theoretical grounds, because oftheir similar chemical characteristics and modes of action we believethat many of the other fatty acids whose general characteristics aresummarised in the previous paragraph will also have similar effects. Theeffects observed include reduced hair loss, reduced suppression ofleukocytes and lymphocytes, reduced nausea and vomiting and inparticular reduced fatigue and malaise. Our observations thereforeindicate that GLA and EPA and related compounds may surprisingly have abroad spectrum of actions in reducing many different side effects ofchemotherapy. We therefore propose their use in patients who arereceiving chemotherapy for cancer to reduce the side effects of suchchemotherapy, as set out in the claims herein.

[0006] We have recently supported the clinical observations by animalstudies on the cardiotoxicity of doxorubicin and the lung toxicity ofbleomycin. When 20 mg of doxorubicin (DOX) is given intraperitoneally tomice, the animals usually die within two weeks because of cardiacdamage. When animals were pre-treated with LA or with GLA or with EPA orwith DHA in various doses and chemical forms, the death rate to the samedose of doxorubicin was reduced to between 20% and 60% depending on thedose and the precise chemical administered. In addition the reduction incardiac weight, which is characteristic of doxorubicin toxicity, wasconsiderably attenuated. Similarly, bleomycin introduced into thetrachea of animals under anaesthesia at a dose of about 5-10 IU per kgbody weight, within 2-4 weeks the animals develop severe lung fibrosiswhich is very similar to the fibrosis which occurs in human patientstreated with bleomycin. Treatment with gamma-linolenic acid and linoleicacid could almost entirely suppress the lung pathological changes andthe increased production of fibrous tissue. In a third animal study, theanti-cancer streptozotocin was used. A major effect of this compound isto damage the islet cells of the pancreas and consequently to lead toinsulin dependent diabetes. Administration of LA, GLA or EPA prior tothe streptozotocin greatly reduced the likelihood of the development ofdiabetes in rats. The ability of the fatty acids to suppress these verydifferent forms of toxicity and the clinical observations which havebeen made in patients being treated with a wide range of drugs suggestthat this is a method of preventing drug toxicity which has wideapplicability.

THE INVENTION

[0007] The invention is as set out in the claims, but broadly lies inthe use, in preparation of a medicament for treating and preventing theside effects of anti-cancer chemotherapy, particularly the side effectscaused by any of the drugs listed herein, of a polyunsaturated fattyacid with a carbon chain length of 14 to 26 and with 2 to 6 double bondsin the molecule in cis or trans configuration, and a method of suchtreatment or prevention wherein said fatty acid is administered.

[0008] Preferred fatty acids are LA, GLA, DGLA, SA, ALA, EPA and DHA,optionally administered or used with other fatty acids.

[0009] The drugs which have been used in anti-cancer chemotherapy inpatients as referred to above include methotrexate, 5-fluorouracil,cyclophosphamide, cisplatin, doxorubicin, taxol and vincristine, but theinvention provides a method of reducing the side effects resulting fromany form of cancer chemotherapy resulting from drugs in any one of theclasses mentioned below, or drugs similar to them which may be developedin the future:

[0010] Folate antagonists such as methotrexate and trimetrexate

[0011] Pyrimidine antagonists such as 5-fluorouracil, fluorodeoxyuridineand azacytidine.

[0012] Purine antagonists such as mercaptopurine, thioguanine,tiazofurin, chloro-deoxyadenosine and pentostatin.

[0013] Sugar modified analogues such as cytarabine and fludarabine.

[0014] Ribonucleotide reductase inhibitors such as hydroxyurea.

[0015] Nitrogen mustards such as mechlorethamine, chlorambucil,melphalan cyclophosphamide and ifosfamide.

[0016] Aziridines such as thiotepa, altretamine and mitomycin.

[0017] Alkane sulfonates such as busulfan.

[0018] Nitrosoureas such as carmustine, lomustine, semustine andstreptozotocin.

[0019] Platinum compounds such as cisplatin and carboplatin.

[0020] Methylating agents such as dacarbazine and procarbazine.

[0021] DNA-binding drugs such as daunorubicin, doxorubicin, idarubicin,epirubicin, mitoxantrone, dactinomycin, bleomycin and plicamycin.

[0022] Topoisomerase inhibitors such as etoposide, teniposide,amascrine, camptothecin.

[0023] Microtubule active agents such as vinblastine, vincristine,vindosine, taxol and taxotere.

[0024] The fatty acids may be administered at the same time as theanti-cancer drugs or preferably both prior to and during therapy withthe anti-cancer drugs themselves administered in amounts appropriate forthe individual drug. The doses of the fatty acids may be from 1 mg to100 g per day, preferably 50 mg to 50 g per day and very preferably 500mg to 20 g per day. The fatty acids may be given in any appropriate formwhich leads to an elevation of the fatty acid in the blood and cellmembranes, including free fatty acids, simple esters of various sorts,salts including lithium salts, mono-, di- and tri-glycerides, mono- anddi-esters of dihydric alcohols, ascorbyl and niacin derivatives,cholesterol esters, phospholipids and any other appropriate carriers.They may be given orally, parenterally or topically using anyappropriate carrier or delivery systems or excipients known to thoseskilled in the art, including capsules, tablets, powders, liquids,emulsions and any other appropriate method.

FORMULATION EXAMPLES

[0025] The chemotherapy drugs can be administered in the mannerconventional for each drug, itself known and no part of the invention.The fatty acids may be in any convenient form and the following areexamples, suited also to the other fatty acids discussed.

[0026] 1. Administration of 500 mg to 20 g of GLA per day in the form ofsoft or hard gelatine capsules or tablets providing:

[0027] a. 40 to 80 mg per capsule of GLA in the form of evening primroseoil.

[0028] b. 50-150 mg per capsule of GLA in the form of borage,blackcurrant, fungal or other appropriate oil.

[0029] c. 100-500 mg GLA per capsule in the form of triglyceride GLA, orany appropriate salt of GLA, such as the lithium or calcium or magnesiumor zinc or potassium salts.

[0030] 2. Administration of DGLA in a dose of 500 mg to 20 g per day inthe forms of 1 g above.

[0031] 3. Administration of GLA or DGLA in association with EPA, with orwithout DHA, for example as a 40 to 80 mg GLA per capsule in the form ofevening primrose oil together with 10 mg to 100 mg per capsule of EPA inthe form of cold water marine fish oil.

[0032] 4. Administration of GLA or DGLA in the form of a soluble powderor effervescent granule formed from any appropriate salt of GLA as in 1c above and excipients such as citric acid monohydrate, sodiumbicarbonate or other dibasic acids such as tartaric or maleic acid plussweeteners such as sucrose or sorbitol and flavourings.

[0033] 5. Administration of GLA or DGLA in the form of liquid eveningprimrose, borage or other appropriate oil as the oil itself or as a whipor emulsion prepared with appropriate flavours and stabilisers known tothose skilled in the art.

[0034] 6. Administration of GLA or DGLA in any appropriate chemicalform, microencapsulated using starch, gelatine, gum arabic or otherappropriate formulation known to those skilled in the art.

[0035] 7. Administration of GLA in the form of pessaries, suppositories,skin patches or any other appropriate route.

[0036] 8. A parenteral lipid emulsion is used containing 10% total lipidby volume in a per se conventional pyrogen-free formulation “INTRALIPID”oil in water emulsion (trade mark, Kabi-Vitrum) containing per 500 mlwater at pH 7: Fractionated Soybean oil 50 g Fractionated eggphospholipids  6 g Glycerol 11 g

[0037] According to the invention (a) 5%, (b) 10% or (c) 15% of thelipid present, by weight, is taken up by one or other of the mixtures ofEFAs below, the EFAs being provided as triglycerides, or free fattyacids, or ethyl esters, or diol esters as in our PCT specifications WO96/34846 (PCT GB 96/01053) and WO 96/34855 (PCT GB 96 01052), orappropriate salts, including the lithium salts. The following figuresshow the proportional composition of the added EFA or EFA mixture: GLADGLA SA EPA DHA 100  — — — — 50 50 — — — 50 — 50 — — 50 — — 30 20 — 60 —20 20 — 80 20 — — 80 — — 20 10 — — — 80 20

[0038] 9. An oil-in-water oral emulsion (batch size 200 g) was preparedcontaining the following ingredients, the galactolipid being asdescribed in PCT specification WO 95/20943 (PCT SE 95/00115):Ingredients % wt. Emulsifier (galactolipid)* 2.00 1,3-Propane dioldiester (GLA-EPA) 20.00 (as in Example 8) Ascorbyl palmitate (AP) 0.02Vitamin E 0.5 Water to 100.00

[0039] The emulsifier-galactolipid was dispersed in the diester, and theVitamin E, AP and water were mixed. The oil phase was added to theaqueous phase under a high shear mix (Ultraturrax—trade mark) at speed4, for a few minutes. This pre-emulsion was then homegenised at 80 MPAand at 50° C. for 6 cycles (mini-Lab 8.30H; APV Rannie AS, Denmark). Theemulsion formed had an average droplet size of 230 nm.

[0040] Case Histories

[0041] The following histories illustrate use of the invention

[0042] A. A patient with malignant brain cancer, a glioblastoma, wastreated in addition to surgery with the nitrosourea, carmustine. Priorto and during the carmustine course the patient was also receivinggamma-linolenic acid and linoleic acid in the form of the triglyceridedilinoleoyl-monogammalinolenoyl-glycerol (DLMG). Carmustine normallycauses marked nausea and vomiting, anorexia and severe malaise incontrast, this patient experienced only very mild nausea and felt wellthroughout indicating reduction of the side effects by the DLMG.

[0043] B. A patient with Hodgkin's disease was treated with the ‘MOPP’regime (carmustine, vincristine, procarbazine and prednisone). For oneweek prior to the start of the chemotherapy regime, and throughout thecourse of chemotherapy, this 40 year old man also received 3 g per dayorally of the lithium salt of gammalinolenic acid. This chemotherapyregime normally causes severe vomiting and nausea, marked malaise andanorexia. In contrast, this patient experienced only mild nausea andremained well and able to continue working

[0044] C. A 50 year old woman with breast cancer was treated with the‘CMF’ regime (cyclophosphamide, methotrexate and 5-fluorouracil). Thisregime was started one week after receiving a cumulative dose of 30 g ofgammalinolenic acid intravenously as the lithium salt with continuedtreatment with 2 g/day of oral lithium gammalinolenate. The chemotherapyregime normally causes nausea, vomiting, mucositis and white cellsuppression. In contrast, this woman experienced only mild nausea withno vomiting or mucositis and the suppression of the white cell count wasless than expected.

[0045] D. A 55 year old man with metastatic colon cancer was treatedwith 5-fluorouracil. This normally causes nausea, vomiting, white cellsuppression and mucositis. For two weeks prior to the chemotherapy andduring the whole of the chemotherapy course, the man also received 3g/day of the pure triglyceride of eicosapentaenoic acid. There was novomiting or mucositis and the nausea and white cell suppression wereless than expected.

1. The use in preparation of a medicament for treating and preventingthe side effects of anti-cancer chemotherapy, particularly the sideeffects caused by any of the drugs listed herein, of a polyunsaturatedfatty acid with a carbon chain length of 14 to 26 and with 2 to 6 doublebonds in the molecule in cis or trans configuration, and a method ofsuch treatment or prevention wherein said fatty acid is used as anactive.
 2. Use or method according to claim 1 wherein the fatty acid isselected from LA, GLA, DGLA, SA, ALA, EPA and DHA, optionallyadministered or used with other fatty acids.
 3. Use or method accordingto claim 1 wherein the drug is doxorubicin or a related compound whichcauses cardiotoxicity.
 4. Use or method according to claim 1 wherein thedrug is bleomycin or a related compound which causes lung toxicity. 5.Use or method according to claim 1 wherein the drug is cisplatin or arelated compound which causes neurotoxicity.
 6. Use or method accordingto claim 1 wherein the drug is doxorubicin or a related compound and thefatty acid is LA, GLA or DGLA, optionally administered or used withother fatty acids.
 7. Use or method according to claim 1 wherein thedrug is bleomycin, cyclophosphamide or a related compound and the fattyacid is LA, GLA or DGLA, optionally administered or used with otherfatty acids.
 8. Use or method according to claim 1 wherein the drug iscisplatin or a related compound and the fatty acid is LA, GLA or DGLA,optionally administered or used with other fatty acids.